Several processes were reported for the synthesis of (S)-Pregabalin. One such process is illustrated in drugs of the future, 24 (8), 862-870 (1999), represented as scheme-1. In which 3-isobutylglutaric acid, compound 2, is converted into the corresponding anhydride, compound 3, by treatment with refluxing acetic anhydride. The reaction of the anhydride with NH4OH produces the glutaric acid mono-amide, compound 4, which is resolved with (R)-1-phenylethylamine, yielding the (R)-phenyl ethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid, compound 5. Combining the salt with an acid liberates the (R)-enantiomer, compound 6. Finally, a Hoffmann's degradation with Br2/NaOH provides (S)-Pregabalin. A disadvantage of this method is that, it requires separating the two enantiomer thereby resulting in the loss of half of the product, such that the process cost is high.

A few stereo selective processes for the synthesis of (S)-Pregabalin have been disclosed. For example, U.S. Pat. No. 5,599,973 discloses the preparation of (S)-Pregabalin using stoichiometric (+)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary that may be recycled. In general, however, that route is of limited use for scale-up, principally due to the low temperature required for the reactions, the use of pyrophoric reagent such as butyl lithium, and due to side reactions, which resulted in a low overall yield.
Another process is disclosed in U.S. Patent Application Publication No. 2003/0212290, which discloses asymmetric hydrogenation of a cyano-substituted olefin, compound 7, to produce a cyano precursor of (S)-3-(amino methyl)-5-methyl hexanoic acid, compound 8, as seen in scheme 2.

Subsequent reduction of the nitrile with compound 8 by catalytic hydrogenation produces (S)-Pregabalin. The cyano hexenoate starting material, compound 7, is prepared from 2-methyl propanal and acrylonitrile (Yamamoto et al, Bull. Chem. Soc. Jap., 58, 3397 (1985)). However, the disclosed method requires carbon monoxide under high pressure, raising serious problems in adapting this scheme for production scale processes.
A process published by G. M. Sammis, et al., J. Am. Chem. Soc., 125(15), 4442-43 (2003), takes advantage of the asymmetric catalysis of cyanide conjugate addition reactions. The method discloses the application of aluminium salen catalysts to the conjugate addition of hydrogen cyanide to α,β-unsaturated imides as shown in scheme-3. Reportedly, TMSCN is a useful source of cyanide that can be used in the place of HCN. Although the reaction is highly selective, this process is not practicable for large scale production due to the use of highly poisonous reagents. Moreover, the last reductive step requires high pressure hydrogen, which only adds to the difficulties required for adapting this scheme for a production scale process.

In 1989, Silverman reported a convenient synthesis of 3-alkyl-4-amino acids compounds in ‘Synthesis’, Vol. 12, 953-954 (1989). Using 2-alkenoic esters as a substrate, a series of GABA analogs were produced by Michael addition of nitro methane to α,β-unsaturated compounds, followed by hydrogenation at atmospheric pressure of the nitro compound to amine moiety as depicted in scheme 4.

Further resolution of compound 14 may be employed to resolve Pregabalin. This, of course, results in the loss of 50 percent of the product, a serious disadvantage. However, the disclosed methodology reveals that the nitro compound can serve as an intermediate for the synthesis of 3-alkyl-4-amino acids.
Due to the activity of GABA as an inhibitory neurotransmitter, and its effect on convulsive states and other motor dysfunction, development of a drug which can stimulate the release of GABA has become important. Pregabalin a GAD activator has the ability to stimulate the release of GABA and to suppress seizures while avoiding the undesirable side effect of ataxia. It has been discovered that anticonvulsant effect of isobutyl-GABA is stereoselective. That is, S-isomer of Pregabalin shows better anticonvulsant activity than the R-stereoisomer. Thus, it would be beneficial to have an efficient process for the synthesis of the (S)-isomer of pregabalin.
The consumption of pregabalin has increased in high volumes and all the reported processes provide very poor yields of (S)-pregabalin. Hence there is a need to develop a method of preparation of pregabalin, which provides high yields, is cost effective and commercially viable, and which can be adapted to an industrial scale.